tbuckley/cabot-search huggingface dataset:
IMMU-54. PNEUMOCYSTIS JIROVECII PNEUMONIA INFECTION IN A PATIENT WITH ANAPLASTIC ASTROCYTOMA AND RADIATION NECROSIS IN THE SETTING OF CORTICOSTEROID AND PEMBROLIZUMAB USE
Authors: Yoon Choi, Xiao-Tang Kong
Journal: Neuro-Oncology (2023)

Abstract We present a case with anaplastic astrocytoma and radiation-induced brain necrosis, diagnosed with pneumocystis jirovecii pneumonia(PJP) while receiving corticosteroid and pembrolizumab, an immune checkpoint inhibitor(ICI). ICIs have significantly changed management of many cancer types and are known to be associated with immune related adverse events(irAEs). Recently, concerns have emerged regarding the potential relationship between ICI use and infection risks, and PJP, a rare opportunistic infection, has been reported in patients with ICI treatments with or without corticosteroid use. A 40-year-old man with anaplastic astrocytoma and radiation-induced brain necrosis on corticosteroid and pembrolizumab presented with high fever and tachycardia over three days, and the patient later developed hypoxia and cough. The patient was on dexamethasone for brain radiation necrosis for two months and he received one dose of pembrolizumab two weeks prior to his symptom onset, based on genetic information that showed hypermutated tumor and abnormal DNA mismatch repair protein expression. Chest CT showed abnormal findings from infectious or inflammatory process. Bronchoalveolar lavage sample confirmed positive pneumocystis jiroveci PCR test, confirmed PJP, and he was treated with clindamycin, primaquine, and prednisone. To the best of our knowledge, this is the first reported case of PJP in a patient with primary brain tumor receiving corticosteroid and pembrolizumab. ICIs are being investigated in patients with primary brain tumors and wildly used in patients with malignancies with frequent central nervous system involvements, such as malignant melanomas and non-small cell lung cancers. Awareness of risk for infectious conditions including PJP in patients on ICI treatment, especially with corticosteroid use is crucial for implementing appropriate prophylactic measures and prompt diagnosis and treatment interventions.
QOL-18. HIGHER VINCRISTINE DOSES CORRELATE WITH LONGER OVERALL SURVIVAL: A POST-HOC ANALYSIS OF PARTICIPANTS RECEIVING PCV ON RTOG 9402
Authors: Laura Donovan, Mei-Yin Polly, J Gregory Cairncross, Andrew Lassman, Fabio Iwamoto, Igor Barani, Luis Souhami, Henry C Pitot, Barbara Fisher, Maria Werner-Wasik, Jean-Paul Bahary, Anthony Whitton, Mark V Mishra, Jiayi Huang, Alan C Hartford, Karen Fink, Normand Laperriere, Minhee Won, Minesh Mehta
Journal: Neuro-Oncology (2023)

Abstract RTOG 9402 demonstrated procarbazine (P), lomustine (CCNU/C), and vincristine (V), collectively PCV, added to radiation therapy significantly improved survival for patients with newly diagnosed anaplastic oligodendroglial tumors. The improvement was most pronounced in 1p19q codeleted cases, and to a lesser extent, IDH-mutant cases, with no survival benefit in cases with neither biomarker. Analogous results were observed in other phase III trials. However, vincristine (V) can cause substantial toxicity and requires intravenous administration, both negatively affecting quality of life, with debatable contribution to PCV efficacy. As a randomized trial comparing PCV to PC is unlikely to be conducted, we explored correlations between survival and V-dosing in patients randomized to PCV in RTOG 9402. We performed post-hoc analyses of all evaluable participants (n = 143) randomized to PCV on RTOG 9402, supplemented by restricting the analyses to the chemosensitive molecular subsets (IDH-mutant and/or 1p/19q codeleted, n = 118). Total V dose by quartile (Q) was calculated. Survival from six months post-randomization was compared among V dose groups, adjusting for age, extent of resection (EOR), and Karnofsky Performances Status (KPS) in a Cox proportional hazards model. Higher V dose received correlated with longer survival in multivariate analyses (n = 134, median-Q3 vs. &amp;lt; Q1, HR 0.40 (0.22, 0.73), p = 0.003; ≥Q3 vs. &amp;lt; Q1, HR 0.39 (0.22, 0.72), p = 0.002). Excluding chemoresistant cases (IDH wild-type/not codeleted), survival was also significantly longer in evaluable participants receiving the highest doses of vincristine (≥Q3 vs. &amp;lt; Q1 HR 0.42 (0.21,0.81), p = 0.01). In this post-hoc analysis, higher overall V-dose received correlated with longer survival in evaluable patients with anaplastic oligodendroglial tumors receiving PCV chemotherapy in RTOG 9402. Of note, as vincristine dosing was not assigned by randomization, confounding due to differences in patient characteristics among V dose groups cannot be ruled out. Caution should be exercised when considering discarding V from the PCV regimen.
BIOM-44. IMPROVED OVERALL SURVIVAL OF RECURRENT GLIOBLASTOMA (GBM) PATIENTS WITH EGFR AMPLIFICATION AND EGFR VIII MUTATIONS TREATED WITH OSIMERTINIB: A RETROSPECTIVE REVIEW
Authors: Joshua Nahm, Eva Highberg Schumann, Mia Vu, Mousumi Sinha, Cornelius Ware, Sigmund Hsu, Jay-Jiguang Zhu
Journal: Neuro-Oncology (2023)

Abstract Glioblastoma (GBM) is the most common primary malignant brain tumor in adults with an overall survival (OS) of 14.6-23 months in clinical trial patients and 11 months for the real world population. There is no uniform standard of care for recurrent GBM (rGBM) patients. EGFR amplification and EGFRvIII mutations are common in GBM and are potential targets with EGFR tyrosine kinase inhibitors (EGFR-TKI). Osimertinib, a third-generation EGFR-TKI, effectively penetrates the blood brain barrier and is FDA-approved for non-small cell lung cancer. We conducted a retrospective review of rGBM patients with EGFR amplification and EGFRvIII mutations who received osimertinib in addition to other therapies such as bevacizumab, irinotecan, tumor-treating fields, and salvage radiation at recurrence. The primary outcome was OS. Secondary outcomes included recurrence free survival (RFS), overall survival after initiation of osimertinib (rOS), and adverse events (AE). Statistical analysis utilized the Kaplan-Meier estimate. AE were defined by the Common Terminology Criteria for Adverse Events Version 5.0. Twenty-seven patients (17 males) with a median age of 59 years (range: 29-75) were identified. All except one patient were IDH1-wild type (92.9%). MGMT promoter statuses included ten methylated (35.71%) and 11 unmethylated patients (39.29%). The median time on osimertinib was 5.1 months. The median OS was 28 months (95% CI 24, NA). Following osimertinib initiation, the median RFS was 6.4 months (95% CI 5.1, NA), and the median rOS was 12 months (95% CI 8.4, NA). AEs included grade I/II rash (44.4%), grade I/II diarrhea (40.7%), grade III leukopenia (18.5%), and grade III thrombocytopenia (11.1%). The data suggests that osimertinib improves the OS of rGBM patients with manageable and reversible AEs. Despite the limitations of a retrospective study and small sample size, osimertinib is a promising targeted therapy for rGBM. Further research is warranted in a clinical trial to evaluate this treatment prospectively.
BIOM-37. EXTRACELLULAR VESICLES AS A PHARMACODYNAMIC REPORTER IN GLIOBLASTOMA
Authors: Valerie DeLuca, Nanyun Tang, Yue Hao, Anjali Raju, Charles Shaffer, Cecile Riviere-Cazaux, Terry Burns, Jann Sarkaria, Ian Parney, Patrick Pirotte, Kendall Van Keuren-Jensen, Michael Berens
Journal: Neuro-Oncology (2023)

Abstract Development of a non-invasive test that can measure drug delivery and target engagement in GBM represents an opportunity to enhance knowledge during early phase clinical trials of a new compound’s pharmacological suitability and potential efficacy. We present here data supporting that the cargo within extracellular vesicles (EV) can potentially serve as a liquid biopsy that reports on the pharmacodynamics of GBM therapeutics. We treated short-term PDX cultures with vehicle, temozolomide, MLN4924, or arsenic trioxide. EVs were isolated from culture supernatants using size exclusion chromatography and then analyzed by mass spectrometry (proteomics) and RNA sequencing to characterize and compare cargo profiles for each condition. We found that at the proteome level, FDFT1 and FARSB were detected only in temozolomide EVs across all cell lines. In addition, there were drug-agnostic indications of exposure, including decreased abundance in all treated EV conditions of SLC3A2, C3, PLG, and A1BG, and increased abundance of GSTP1. These cargo changes were further validated by western blotting and ExoView immunofluorescence on isolated EVs. At the EV-transcriptome level, depending on treatment, there were shared alterations in EV cargo between models in the expression of long non-coding RNAs, genes that are overrepresented in biological processes such as cytoplasmic translation and cellular macromolecule biosynthesis, and circular RNAs. Thus, these results indicate that EV cargo post-treatment may be a novel pharmacodynamic reporter in GBM. To allow immunoprecipitation of patient GBM-derived EVs with the selective interrogation, the potential biomarkers, including PTPRZ1, B7H3, IL13RA2, and EGFR were screened across isolated EVs from both pre-clinical and clinical patient samples. Future efforts are focused on evaluating immunoprecipitated GBM-EVs from longitudinally collected patient biofluids. Overall, we anticipate that the results of this study will lead to development of a clinical test that reflects BBB penetration and tumor response, which will likely aid in novel drug development efforts.
EXTH-05. ANTI-TUMOR IMMUNE RESPONSE OF ONCOMAGNETIC MONOTHERAPY IN GLIOBLASTOMA
Authors: Arvind Pandey, Shashank Hambarde, David S Baskin, Santosh A Helekar
Journal: Neuro-Oncology (2023)

Abstract BACKGROUND Glioblastoma (GBM) is the most lethal primary malignant brain tumor with a median survival of 15–20 months. Concurrent temozolomide (TMZ) chemotherapy and radiation (XRT) remain the current standard of care (SOC) treatment for newly diagnosed GBM. The addition of tumor treating fields (TTFs) improves median survival for newly diagnosed GBM from 16 to 20.9 months. This modest improvement underscores the urgent need to identify a new treatment modality as a safe and effective therapy. PURPOSE The noninvasive Oncomagnetic device developed in our laboratory selectively kills glioblastoma (GBM) in vitro by generating the spinning oscillating magnetic field (sOMF) which disrupts electron transport chain, leading to a marked increase in reactive oxygen species (ROS) and consequently to cancer cell death. We studied the cellular and molecular effects of sOMF treatment on GBM cell lines and investigated the immune response to Oncomagnetic monotherapy (OMT) in a syngeneic mouse model. RESULTS sOMF significantly reduces cell proliferation and cell survival in vitro . It induces DNA damage and arrests cells in G1-phase of the cell cycle. Whole-body sOMF stimulation caused a substantial retardation of tumor growth and reduction of the contrast-enhanced tumor volume in 9.4T MRI scans. OMT showed significant increase in overall survival in treated mice. We also observed upregulated immune response indicated by RNA sequencing data obtained from sOMF-treated LN229 cells as well as in treated GBM mouse tumor sections by imaging mass cytometry analysis. The tSNE analysis of various immune clusters suggests significant increase in immune response by activating CD4+, CD8+, murine-macrophages and M1-macrophages located at tumor site in the treated group. CONCLUSION The obtained data indicate significant anti-tumor response by inhibiting cancer signaling pathways and an increased immune response. Our findings suggest unique mechanism of action for sOMF stimulation and provide a strong rationale for standalone OMT for GBM.
CCRG-04. AUTOMATED REAL TIME TRACKING OF GLIOBLASTOMA CELL CYCLE TRANSITIONS IN ASSEMBLOIDS LINKS G2 CELLS TO INFILTRATION
Authors: Christopher Yusuf Akhunbay-Fudge, Kevin Critchley, Ryan Mathew, Heiko Wurdak
Journal: Neuro-Oncology (2023)

Abstract Glioblastoma (GB) is the most aggressive primary brain tumour in adults associated with survival rates below 5% despite treatment. Tumour repopulating residual cells in the surgical cavity resist treatment due to their molecular heterogeneity. Single-cell transcriptomic studies have linked GB heterogeneity to the cell cycle; however, it remains unclear to what extent cell cycle states affect the infiltrative capacity of GB. The “go or grow” paradigm predicts that migration and proliferation are separate spatiotemporal events. We used a brain tumour-cerebral organoid (assembloid) approach to test the migratory potential of GB cell cycle phases during assembloid infiltration. Human induced pluripotent cells were differentiated into cerebral organoids that self-assemble with spheroids of patient-derived GB cells, expressing a fluorescent cell cycle reporter (FUCCI). Utilising live-cell confocal imaging, the process of GB assembloid infiltration was captured. Resultant videos were analysed with automated image analysis capable of tracking cell cycle transitions and cellular migration in confocal microscopy planes, enabling the longitudinal quantification of GB migration and invasion. Our analysis revealed a subset of highly infiltrative GB cells, containing a significant number of cycling G2 phase cells that demonstrated a ~1.4-fold increase in directional infiltrative capacity compared to their non cycling G1 phase counterparts. To isolate and characterize the G2 migratory GB cell state, we developed a phenotypic separation assay using microenvironmental cues. Specifically, we found that these cues markedly affect GB migration routes enabling the isolation of the highly migratory GB cells for further investigation. Our results question the “go or grow” hypothesis at the level of GB cellular subpopulations. We hypothesise that the observed G2 migratory capacity of GB cells could be critical to tumour recurrence following surgery. Further research is underway to define the underlying mechanisms of G2 GB cell migration.
CTIM-16. DEVELOPING PATIENT SPECIFIC TUMOR INFILTRATING LYMPHOCYTES (TILS) WITH INCREASED TUMOR SPECIFICITY AS A THERAPY FOR GLIOBLASTOMA
Authors: Kelly Hotchkiss, Emily Blandford, Pamela Noldner, Ying Zhou, Kirit Singh, Anoop Patel, Peter Fecci, Scott Antonia, Beth Shaz, Mustafa Khasraw
Journal: Neuro-Oncology (2023)

Abstract Immunotherapy failure in glioblastoma results from three main hurdles; limited numbers of T cells within the tumor, T cell exhaustion and significant intra-tumoral and intra-patient heterogeneity leading to lack of T cell tumor recognition. Our group has developed an expansion protocol to isolate and expand less exhausted tumor infiltrating lymphocytes (TILs) from the tumor periphery, selecting for TILs that recognize tumor antigen ex vivo. This process will increase the number of T-cells specific for an individual patient’s diverse tumor neoantigens. We have successfully expanded glioblastoma associated TILs from 66% of the novel Lukens trap substrate, which collects TILs and tumor from the tumor periphery. Cells are expanded in two stages, preREP and REP, through novel methods based on a protocol with clinical success in lung cancer and modified to increase the percent of tumor specific T cells. Through co-culture with patient matched glioma neurospheres we have identified activated T cells from each stage of culture (initial product, preREP, REP) based on CD137+ expression and tumor specific cytokine release (IFNy+TNFa+IL2+IL17a+) by flow cytometry. Through 5’scRNA sequencing paired with TCR repertoire analysis we can identify activation specific TCRs. Overrepresented TCR alpha and beta chains will be linked by a P2A site, cloned into a lentiviral vector, and transduced into TCR negative Jurkat cells to confirm tumor reactivity. This strategy will allow us to enrich and assess tumor specific TCR activity compared to bystander activation in our TIL product. Following additional preclinical assessment of cytotoxicity against autologous tumor, we will evaluate safety and feasibility of by administering our novel TIL product intrathecally in patients with glioblastoma.
CTNI-49. RHENIUM-(RE-186)-OBISBEMEDA [RE-186-NANOLIPOSOME] (186RNL) PHASE 2 FOR RECURRENT GLIOBLASTOMA (RGBM) VIA CONVECTION ENHANCE DELIVERY [CED]
Authors: Andrew Brenner, Joel Michalek, Melissa Moore, Marc Hedrick, Ande Bao, William Phillips, Toral Patel, Jeffrey Weinberg, John Floyd
Journal: Neuro-Oncology (2023)

Abstract BACKGROUND The Phase 1 ReSPECT-GBM trial observed a relative improvement in overall survival(OS) in rGBM with absorbed doses &amp;gt;100 Gray[Gy] compared to lower doses and historical controls. Statistical modeling was employed to understand the dose response relationship in planning the Phase2 trial. METHODS Phase1 data from cohorts1-6 of the 3 + 3 dose-escalation trial[N = 21] were utilized. Longitudinal MRI and SPECT/CT imaging were performed to assess treatment outcomes. SPECT/CT images were used to find the treatment volume. Variation in survival significance was assessed with log rank tests and an accelerated failure time (AFT) model. All statistical testing was 2-sided with a 5% significance level. RESULTS MTD/DLT was not reached in the first 6 cohorts. The 3 + 3 dosing (ml&amp;mCurie) by cohort was 1: 0.66&amp;1.0, 2: 1.32&amp;2.0, 3: 2.63&amp;4.0, 4: 5.28&amp;8.0, 5: 5.28&amp;13.4, 6: 8.8&amp;22.3. Unadjusted for covariate information, median OS was 11.0 months(m) [95% Confidence Interval (CI) 5.0 m to 17 m]. Median OS varied significantly with absorbed dose; &amp;lt; 100 Gy: n = 9, median OS = 6.0 m, 95% CI 1.0m to 11m), ≥100 Gy: n = 12, median OS = 17.0 m (95% CI 8.0 m to 35.0 m), p &amp;lt; 0.001. After adjustment for age, baseline ECOG performance status, and baseline tumor volume, the AFT model predicted the OS to fold increase by 1.3 (95% CI 1.1 to 1.5)/100Gy increase in the absorbed dose (p &amp;lt; 0.001) and by 1.28 (95% CI 1.21 to 1.35 m)/10% increase in the treated to total tumor volume ratio (p &amp;lt; 0.001). The phase 2 trial, utilizing Cohort6 administered dose 22.3mCi in 8.8mL for tumor volumes ≤20mL [average absorbed dose of 374.5Gy], is ongoing--n = 5 accrued as of May 2023. CONCLUSION 186RNL therapy resulted in a dose and volume dependent impact on OS without significant toxicity. Based on these data, the Cohort 6 non-DLT dose advanced to Phase 2. Study progress will be reported.
EPCO-05. SPATIOTEMPORAL MODELLING OF GLIOBLASTOMA FOR DRUG PREDICTION
Authors: Varsha Thoppey Manoharan, Aly Abdelkareem, Katalin Osz, Jennifer Chan, Sorana Morrissy
Journal: Neuro-Oncology (2023)

Abstract Glioblastoma (GBM) is a lethal primary brain malignancy characterized by inevitable relapse. Understanding intra-tumoral heterogeneity and the microenvironmental influence on tumor progression is key to developing effective therapies. We employ 10X Genomics’ Visium Spatial Transcriptomics platform to study murine xenograft models of multi-regional and longitudinally derived cell lines from 4 GBM patients. This resource enables the study of tumor growth at spatial resolution and allows robust species-specific distinction of tumor and its microenvironment (TME). Using a matrix factorization approach, we delineate spatial gene expression programs (GEP) specific to the tumor and TME. We observe unique niches including progenitor cell-states along the leading edge (LE) of the tumor, oligodendrocyte-like (OC) and astrocytic-like (AC) states at the tumor core along with tumor-associated endothelial states. At early time-points, the homing of brain-resident microglia (MG), macrophages (BMDM), reactive astrocytes to the tumor site are observed. The invasiveness of GBM is a major obstacle, as these cells are therapeutically resistant and seed recurrence. Targeting the LE of GBM could therefore improve patient outcomes. Interestingly in our models, the LE state exhibits higher patient diversity; upregulation of ligand/receptor genes in secreted phosphoprotein, fibronectin, macrophage migration pathways highlighting prospective targets. Further, we analyzed protein-protein interaction networks of the LE programs, which revealed that upregulation of “hub genes” within the network significantly reduces patient survival. Further investigation of such program-specific vulnerabilities will help inform on combinatorial therapeutic strategies to control disease progression and paves the way for future testing of treatment response in both xenografts and syngeneic models.
CTNI-64. EFFICACY AND SAFETY OF ERDAFITINIB IN PATIENTS WITH HIGH-GRADE AND LOW-GRADE GLIOMAS AND PRESPECIFIED FIBROBLAST GROWTH FACTOR RECEPTOR ALTERATIONS (FGFRALT) IN THE RAGNAR TRIAL
Authors: David Reardon, Liam Welsh, Kent Shih, Toshio Shimizu, Jean-Charles Goeminne, Birgit Geoerger, Capucine Baldini, Christophe Massard, Yohann Loriot, Shubham Pant, Sameer Farouk Sait, Shibu Thomas, Constance Hammond, Saltant Najmi, Spyros Triantos, Lauren Crow, Hussein Sweiti, Olaf Witt
Journal: Neuro-Oncology (2023)

Abstract BACKGROUND Erda is an oral selective pan-FGFR tyrosine kinase inhibitor approved to treat adults with locally advanced/metastatic urothelial carcinoma with susceptible FGFR3/2alt who have progressed during/after ≥1 line of platinum-based chemotherapy. RAGNAR interim results demonstrated tumor-agnostic efficacy in adults/adolescents with previously-treated advanced solid tumors with prespecified FGFRalt. Here we report results for patients with HGG/LGG. METHODS Patients with HGG/LGG harboring prespecified FGFR1-4alt (mutations/fusions), disease progression after ≥1 line of systemic therapy, and who exhausted standard therapies received oral erda until disease progression or intolerable toxicity. Primary endpoint: ORR by independent review committee (IRC). Secondary endpoints: DOR, disease control rate (DCR), investigator-assessed efficacy, and safety. Response was based on RANO criteria. RESULTS At data cutoff, 37 HGG (n = 30)/LGG (n = 7) patients received erda. In HGG (glioblastoma, n = 25 [83%]; median (m) age 54.5y [range 13-70]), 29 (97%) had FGFR fusions (FGFR3-TACC3, n = 24); all (100%) underwent initial resection (if feasible) and received radiotherapy/chemotherapy per institution (eg, Stupp protocol); patients received median 2 prior therapies (range 1-6; 37% with prior bevacizumab). ORR in HGG was 10% by IRC (95%CI, 2-27) and 20% by Investigator (95%CI, 8-39); mDOR was not reached (m-F/U, 18.0mo); DCR was 57% (95%CI, 37-75). In LGG (m-age 22y; range 12-32), 4 (57%) had FGFR1 mutation (all FGFR1-K656E); 3 (43%) had FGFR fusion. ORR in LGG was 29% by IRC (95%CI, 4-71) and 14% by Investigator (95%CI, 0-58); mDOR was not reached; DCR was 71% (95%CI, 29-96). 17 HGG patients (57%) had TERT co-alterations; 9 (30%) had PTEN deletions. No HGG/LGG patients had IDH1/2 mutations. Most common (≥40%) adverse events (AEs): hyperphosphatemia, diarrhea, dry skin, dry mouth. 43% had serious AEs (treatment-related, 16%). 19% discontinued due to AEs. No treatment-related deaths occurred. CONCLUSIONS Erda demonstrated clinically meaningful activity in heavily pre-treated HGG/LGG with FGFRalt. Safety was consistent with known safety profile of erda.